A clustering method for robust and reliable large scale functional and structural protein sequence annotation

Bioinformatics, in the last few decades, has played a fundamental role to give sense to the huge amount of data produced. Obtained the complete sequence of a genome, the major problem of knowing as much as possible of its coding regions, is crucial. Protein sequence annotation is challenging and, due to the size of the problem, only computational approaches can provide a feasible solution. As it has been recently pointed out by the Critical Assessment of Function Annotations (CAFA), most accurate methods are those based on the transfer-by-homology approach and the most incisive contribution is given by cross-genome comparisons. In the present thesis it is described a non-hierarchical sequence clustering method for protein automatic large-scale annotation, called “The Bologna Annotation Resource Plus” (BAR+). The method is based on an all-against-all alignment of more than 13 millions protein sequences characterized by a very stringent metric. BAR+ can safely transfer functional features (Gene Ontology and Pfam terms) inside clusters by means of a statistical validation, even in the case of multi-domain proteins. Within BAR+ clusters it is also possible to transfer the three dimensional structure (when a template is available). This is possible by the way of cluster-specific HMM profiles that can be used to calculate reliable template-to-target alignments even in the case of distantly related proteins (sequence identity < 30%). Other BAR+ based applications have been developed during my doctorate including the prediction of Magnesium binding sites in human proteins, the ABC transporters superfamily classification and the functional prediction (GO terms) of the CAFA targets. Remarkably, in the CAFA assessment, BAR+ placed among the ten most accurate methods. At present, as a web server for the functional and structural protein sequence annotation, BAR+ is freely available at http://bar.biocomp.unibo.it/bar2.0.

Geological and hydrogeological features affecting migration, multi-phase partitioning and degradation of chlorinated hydrocarbons through unconsolidated porous media.

Chlorinated solvents are the most ubiquitous organic contaminants found in groundwater since the last five decades. They generally reach groundwater as Dense Non-Aqueous Phase Liquid (DNAPL). This phase can migrate through aquifers, and also through aquitards, in ways that aqueous contaminants cannot. The complex phase partitioning to which chlorinated solvent DNAPLs can undergo (i.e. to the dissolved, vapor or sorbed phase), as well as their transformations (e.g. degradation), depend on the physico-chemical properties of the contaminants themselves and on features of the hydrogeological system. The main goal of the thesis is to provide new knowledge for the future investigations of sites contaminated by DNAPLs in alluvial settings, proposing innovative investigative approaches and emphasizing some of the key issues and main criticalities of this kind of contaminants in such a setting. To achieve this goal, the hydrogeologic setting below the city of Ferrara (Po plain, northern Italy), which is affected by scattered contamination by chlorinated solvents, has been investigated at different scales (regional and site specific), both from an intrinsic (i.e. groundwater flow systems) and specific (i.e. chlorinated solvent DNAPL behavior) point of view. Detailed investigations were carried out in particular in one selected test-site, known as “Caretti site”, where high-resolution vertical profiling of different kind of data were collected by means of multilevel monitoring systems and other innovative sampling and analytical techniques. This allowed to achieve a deep geological and hydrogeological knowledge of the system and to reconstruct in detail the architecture of contaminants in relationship to the features of the hosting porous medium. The results achieved in this thesis are useful not only at local scale, e.g. employable to interpret the origin of contamination in other sites of the Ferrara area, but also at global scale, in order to address future remediation and protection actions of similar hydrogeologic settings.

Development and characterization of deep learning techniques for neuroimaging data

Deep learning methods are extremely promising machine learning tools to analyze neuroimaging data. However, their potential use in clinical settings is limited because of the existing challenges of applying these methods to neuroimaging data. In this study, first a data leakage type caused by slice-level data split that is introduced during training and validation of a 2D CNN is surveyed and a quantitative assessment of the model’s performance overestimation is presented. Second, an interpretable, leakage-fee deep learning software written in a python language with a wide range of options has been developed to conduct both classification and regression analysis. The software was applied to the study of mild cognitive impairment (MCI) in patients with small vessel disease (SVD) using multi-parametric MRI data where the cognitive performance of 58 patients measured by five neuropsychological tests is predicted using a multi-input CNN model taking brain image and demographic data. Each of the cognitive test scores was predicted using different MRI-derived features. As MCI due to SVD has been hypothesized to be the effect of white matter damage, DTI-derived features MD and FA produced the best prediction outcome of the TMT-A score which is consistent with the existing literature. In a second study, an interpretable deep learning system aimed at 1) classifying Alzheimer disease and healthy subjects 2) examining the neural correlates of the disease that causes a cognitive decline in AD patients using CNN visualization tools and 3) highlighting the potential of interpretability techniques to capture a biased deep learning model is developed. Structural magnetic resonance imaging (MRI) data of 200 subjects was used by the proposed CNN model which was trained using a transfer learning-based approach producing a balanced accuracy of 71.6%. Brain regions in the frontal and parietal lobe showing the cerebral cortex atrophy were highlighted by the visualization tools.

Comparing Different Approaches for Clustering Categorical Data

There are different ways to do cluster analysis of categorical data in the literature and the choice among them is strongly related to the aim of the researcher, if we do not take into account time and economical constraints. Main approaches for clustering are usually distinguished into model-based and distance-based methods: the former assume that objects belonging to the same class are similar in the sense that their observed values come from the same probability distribution, whose parameters are unknown and need to be estimated; the latter evaluate distances among objects by a defined dissimilarity measure and, basing on it, allocate units to the closest group. In clustering, one may be interested in the classification of similar objects into groups, and one may be interested in finding observations that come from the same true homogeneous distribution. But do both of these aims lead to the same clustering? And how good are clustering methods designed to fulfil one of these aims in terms of the other? In order to answer, two approaches, namely a latent class model (mixture of multinomial distributions) and a partition around medoids one, are evaluated and compared by Adjusted Rand Index, Average Silhouette Width and Pearson-Gamma indexes in a fairly wide simulation study. Simulation outcomes are plotted in bi-dimensional graphs via Multidimensional Scaling; size of points is proportional to the number of points that overlap and different colours are used according to the cluster membership.

Data-stream driven Fuzzy-granular approaches for system maintenance

Intelligent systems are currently inherent to the society, supporting a synergistic human-machine collaboration. Beyond economical and climate factors, energy consumption is strongly affected by the performance of computing systems. The quality of software functioning may invalidate any improvement attempt. In addition, data-driven machine learning algorithms are the basis for human-centered applications, being their interpretability one of the most important features of computational systems. Software maintenance is a critical discipline to support automatic and life-long system operation. As most software registers its inner events by means of logs, log analysis is an approach to keep system operation. Logs are characterized as Big data assembled in large-flow streams, being unstructured, heterogeneous, imprecise, and uncertain. This thesis addresses fuzzy and neuro-granular methods to provide maintenance solutions applied to anomaly detection (AD) and log parsing (LP), dealing with data uncertainty, identifying ideal time periods for detailed software analyses. LP provides deeper semantics interpretation of the anomalous occurrences. The solutions evolve over time and are general-purpose, being highly applicable, scalable, and maintainable. Granular classification models, namely, Fuzzy set-Based evolving Model (FBeM), evolving Granular Neural Network (eGNN), and evolving Gaussian Fuzzy Classifier (eGFC), are compared considering the AD problem. The evolving Log Parsing (eLP) method is proposed to approach the automatic parsing applied to system logs. All the methods perform recursive mechanisms to create, update, merge, and delete information granules according with the data behavior. For the first time in the evolving intelligent systems literature, the proposed method, eLP, is able to process streams of words and sentences. Essentially, regarding to AD accuracy, FBeM achieved (85.64+-3.69)%; eGNN reached (96.17+-0.78)%; eGFC obtained (92.48+-1.21)%; and eLP reached (96.05+-1.04)%. Besides being competitive, eLP particularly generates a log grammar, and presents a higher level of model interpretability.